Method for manufacturing acetaminophen preparation
Inventors
Sakamoto, Hiroshi • KOMAI, Kunio • Sakakibara, Kenji • BANBA, Hirokazu • Fukuda, Kiyoshi
Assignees
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Publication Number
US-11433031-B2
Publication Date
2022-09-06
Expiration Date
Abstract
A method for manufacturing a preparation which contains acetaminophen at a high content, in particular, a miniaturized tablet (conventional tablets, sustained-release tablets, etc.) which have excellent elution properties, preferable hardness and high drug content uniformity, and a premix drug substance of acetaminophen which has improved manufacturability. According to the method in which acetaminophen having a preset particle size is used for manufacturing a preparation, the flowability of acetaminophen can be improved so that secondary agglomeration can be suppressed and manufacturing efficiency can be elevated. Thus, this method is highly useful for manufacturing an acetaminophen preparation having improved administrability, for example, a reduced size.
Core Innovation
The invention relates to a method for manufacturing a premix drug substance using unpulverized acetaminophen having a defined particle size distribution, where d10 is 5 to 300 μm, d50 is about 120 to about 500 μm, and d90 is 200 to 900 μm. The method includes blending a dispersant and optionally a solubilizing agent into unpulverized acetaminophen in specified amounts, followed by deagglomeration and/or sizing. The process makes the dispersant, or the dispersant and the solubilizing agent, disperse and adhere in and onto the surfaces of acetaminophen particles uniformly to make powder.
A central aspect is that the process prevents deterioration of agglomeration and poor flowability. The dispersant is at least one of hydrated silicon dioxide or light anhydrous silicic acid. The blending and subsequent deagglomeration and/or sizing are used to address performance related to agglomeration behavior and flowability for the manufactured premix drug substance.
The disclosed approach further supports drug substance embodiments in which acetaminophen premixes and tablet formulations are produced using the characterized acetaminophen powder. The described embodiments include comparative evaluations reporting improved flowability and electrostatic charging behavior, and improved elution performance meeting a JP elution standard within a specified time window, with elution measured by HPLC.
Claims Coverage
The independent claim covers a manufacturing method for a premix drug substance using unpulverized acetaminophen with specified particle size distribution, a defined blending of a dispersant and optionally a solubilizing agent, and a subsequent deagglomeration and/or sizing step to uniformly disperse and adhere the additives to particle surfaces while preventing deterioration of agglomeration and poor flowability. It includes additional refinement through dependent claims that narrow particle size distributions and specify dispersant/solubilizing agent identities.
Premix drug substance manufacturing with specified acetaminophen particle size distribution
A method includes blending into unpulverized acetaminophen having a particle size distribution where d10 is 5 to 300 μm, d50 is about 120 to about 500 μm, and d90 is 200 to 900 μm in an amount of 90 to 99.9% by weight relative to 100% by weight of the premix drug substance, and then carrying out deagglomeration and/or sizing.
Blending a dispersant and optional solubilizing agent into unpulverized acetaminophen
Blending a dispersant in an amount of 0.1 to 3% relative to 100% by weight of the premix drug substance and optionally a solubilizing agent in an amount of 0 to 0.8% by weight relative to 100% by weight of the premix drug substance into unpulverized acetaminophen.
Uniform dispersion and adhesion of additives onto particle surfaces via deagglomeration and/or sizing
Deagglomeration and/or sizing is carried out to disperse and make adhere the dispersant, or the dispersant and the solubilizing agent, in and onto the surfaces of the acetaminophen particles uniformly to make powder.
Preventing deterioration of agglomeration and poor flowability
The process prevents deterioration of agglomeration and poor flowability.
Dispersant limited to hydrated silicon dioxide or light anhydrous silicic acid
The dispersant is at least one of hydrated silicon dioxide or light anhydrous silicic acid.
Narrowing particle size distribution for the manufactured premix drug substance
The method includes manufacturing a premix drug substance characterized by a particle size distribution where d10 is 10 to 200 μm and d90 is 250 to 800 μm.
Hydrated silicon dioxide as a specific dispersant option
The manufacturing method is characterized by using hydrated silicon dioxide as the dispersant.
Solubilizing agent limited to macrogol or sodium lauryl sulfate
The solubilizing agent is either macrogol or sodium lauryl sulfate.
Across the independent claim and its dependent refinements, the coverage centers on manufacturing a premix drug substance from unpulverized acetaminophen with specified d10/d50/d90 ranges, blending defined quantities of a dispersant (hydrated silicon dioxide or light anhydrous silicic acid) and optionally a solubilizing agent, and then using deagglomeration and/or sizing to uniformly disperse and adhere the additives to particle surfaces while preventing deterioration of agglomeration and poor flowability. Dependent claims further narrow d10/d90 and specify alternative dispersant/solubilizing agent identities.
Stated Advantages
Prevents deterioration of agglomeration and poor flowability.
Improves flowability, as characterized in comparative evaluations (e.g., angle of repose and reduced adhesion/collection rate).
Improves elution performance meeting a JP elution standard within a specified time window (measured by HPLC).
Documented Applications
Manufacturing a premix drug substance using unpulverized acetaminophen with the defined particle size distribution and blended additives.
Tablet-related embodiments including production of tablets/premix drug substance embodiments for which elution performance meeting JP elution standard is reported.
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